Maria Grazia Pieroni

Protective effect of inhaled furosemide on allergen-induced early and late asthmatic reactions.

The movement of ions and water across the membranes of bronchial cells is part of the control of the bronchial obstructive response to physical stimuli. In a double-blind, randomized, crossover study, we compared the effect of an aerosol of the loop diuretic furosemide with that of a placebo on the early (within 60 minutes) and late (4 to 12 hours) asthmatic responses to a specific inhaled allergen. We studied 11 subjects with mild allergic asthma, who had both early and late asthmatic responses to a specific inhaled allergen in a preliminary challenge. After placebo administration, the maximal changes (mean +/- SE) from base line in the forced expiratory volume in one second (FEV1) and specific airway resistance were, respectively, a decrease of 35 +/- 4 percent and an increase of 288 +/- 56 percent between 0 and 60 minutes after inhalation of the allergen (early response) and a decrease of 35 +/- 5 percent and an increase of 301 +/- 40 percent between 4 and 12 hours (late response). After furosemide administration (4 ml; 10 mg per milliliter), the early response to inhaled allergen was markedly attenuated in all the subjects, and the late response in all but one. The maximal changes in the FEV1 and specific airway resistance were, respectively, a decrease of 11 +/- 2 percent and an increase of 61 +/- 2 percent between 0 and 60 minutes and a decrease of 20 +/- 4 percent and an increase of 178 +/- 25 percent between 4 and 12 hours (P less than 0.05 for all comparisons). No significant differences were seen in the bronchoconstrictor response to inhaled methacholine after furosemide or placebo administration. We conclude that a furosemide-sensitive mechanism in the airways is involved in the pathogenesis of the reactions of patients with allergic asthma. Whether inhaled furosemide might be useful in the treatment of allergic asthma is uncertain and will require further study.

Efficacy and Tolerability of Nimesulide in Asthmatic Patients Intolerant to Aspirin

SummaryInflammation of the airways accompanied by eosinophil infiltration appears to play a fundamental role in the pathogenesis of bronchial asthma. Therefore, anti-inflammatory agents (at present corticosteroids, cromoglycate and nedocromil) are the first-line treatment for this condition. Nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin (acetylsalicylic acid) and indomethacin, however, have never been used in this setting, mainly for fear of adverse effects (e.g. severe obstructive reactions); these can occur, in a consistent number of patients as a consequence (according to the most widely accepted theory) of inhibition of prostaglandin synthesis. In a double-blind crossover placebo-controlled study involving 20 aspirin-sensitive patients with asthma, we found that oral nimesulide 100mg was well tolerated both clinically and functionally (no significant changes in forced expiratory volume in 1 second and specific airway resistance after drug intake). In a more recent study, we observed a mild obstructive reaction (easily controlled with inhaled bronchodilators) after oral administration of nimesulide 400mg to 3 patients who had previously tolerated a 100mg dose. On the basis of clinical experience, nimesulide (unlike most other NSAIDs) in the recommended doses appears to be well tolerated in aspirin-sensitive asthmatic patients. Furthermore, this distinctive anti-inflammatory agent might provide a novel approach to the treatment of bronchial asthma.

Prevention of antigen-induced early obstructive reaction by inhaled furosemide in (atopic) subjects with asthma and (actively sensitized) guinea pigs

The present study was undertaken to determine the effect of furosemide on antigen-induced bronchoconstriction. Ten patients with stable asthma (eight men and two women), aged 17 to 48 years, were challenged with the same dose of allergen (Dermatophagoides pteronissinus, Parietaria, and grass mix) that had induced an FEV1 fall of at least 20% in a preliminary study on two occasions: immediately after placebo and furosemide (approximately 28 mg) administered by inhalation in random order and double-blind. Furosemide did not demonstrate any direct bronchodilator effect but markedly attenuated allergen-induced bronchoconstriction. The mean (95% confidence interval) maximum fall in FEV1 was 31.5% (40.2% to 22.8%) after placebo and 8.4% (11.8% to 4.9%) after furosemide administration. Furosemide, administered by aerosol to anesthetized guinea pigs actively sensitized to ovalbumin, dose dependently protected the animals from anaphylactic reaction. Infusion of furosemide (10 mg/kg for 10 minutes) failed to protect the animals from the anaphylactic response. In nonsensitized guinea pigs, the cardiovascular and pulmonary changes induced by histamine (10 micrograms/kg intravenously [i.v.]), leukotriene C4 (1 micrograms/kg i.v.), and platelet-activating factor (0.1 microgram/kg i.v.) were not modified by aerosol administration of furosemide (10 mg/ml for 10 minutes). In conclusion, inhaled furosemide induces a clear-cut protection against immediate obstructive reaction caused by areoallergerns and ovalbumin, both in subjects with asthma and actively sensitized guinea pigs, respectively.

Quality of life, anxiety and depression in Sarcoidosis

OBJECTIVES This study sought to evaluate the quality of life and the presence of psychiatric disorders in patients with sarcoidosis. METHODS Data were collected from 80 consecutive outpatients with sarcoidosis presenting to the Sarcoidosis Center of the Respiratory Diseases Division at the University of Siena, Italy. RESULTS Forty-four percent of the subjects endorsed at least one psychiatric DSM-IV axis I diagnosis. Specifically, 25% of subjects met the criteria for Major Depressive Disorder, 6.3% for Panic Disorder, 6.3% for Bipolar Disorder, 5% for Generalized Anxiety Disorder and 1.3% for Obsessive Compulsive Disorder. Statistically significant correlations were found between Forced Expiratory Volume in the first second (FEV(1)), Forced Vital Capacity (FVC) and several domains of the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) questionnaire. Subjects with multi-systemic involvement, with asthenia and with a more severe radiographic stage and subjects receiving steroids, reported a poorer quality of life. CONCLUSIONS Sarcoidosis is associated with a high rate of psychiatric comorbidity and may contribute to a poorer quality of life. A referral for a psychiatric or psychological evaluation and counseling should be considered for many of the sarcoidosis patients.

Steroid-sparing effect of inhaled lysine acetylsalicylate and furosemide in high-dose beclomethasone–dependent asthma

BACKGROUND Inhaled lysine acetylsalicylate and furosemide exert a mutually potentiating protective activity on experimentally induced bronchoconstriction in asthma. OBJECTIVE Our purpose was to investigate the clinical effectiveness of combined treatment of asthma with inhaled lysine acetylsalicylate and furosemide. METHODS We performed a randomized, double-blind, crossover study in nine patients with chronic asthma requiring a high dose (2 mg/day) of inhaled beclomethasone for clinical control. Patients were treated with a combination of 720 mg inhaled lysine acetylsalicylate and 40 mg furosemide twice daily, or with matched placebo in addition to inhaled steroids. The dose of inhaled steroids was reduced by half every 15 days and eventually suspended unless a patients respiratory condition worsened. RESULTS During treatment with placebo, all patients had worsening of asthma at dosages of 1 or 0.5 mg/day beclomethasone (mean +/- SE, 833 +/- 83 micrograms/day). During combined treatment complete suspension of inhaled steroids in two patients and reduction to 0.5 to 0.25 mg in the remaining seven patients (mean, 250 +/- 72 micrograms/day) was achieved, with a mean reduction of 71% +/- 7%. Forced expiratory volume in 1 second, weekly peak expiratory flow rate, symptom score, and bronchodilator intake remained significantly better with combined treatment than with placebo. CONCLUSIONS Treatment with inhaled lysine acetylsalicylate and furosemide allows a considerable sparing of inhaled steroids without significant side effects in patients with severe asthma.

Protective activity of inhaled nonsteroidal antiinflammatory drugs on bronchial responsiveness to ultrasonically nebulized water

Relatively high doses of oral aspirin are needed to afford a significant protective effect against the bronchial obstructive reaction to ultrasonically nebulized distilled water (UNDW) in asthmatic patients. Sodium salicylate at similar doses and indomethacin at normal dose afford no protection. The present study was undertaken to assess the protective activity of these drugs taken by inhalation. Thirteen asthmatic patients performed two UNDW challenges 20 minutes and 24 hours after inhalation of 900 mg lysine acetylsalicylate (L-ASA) or placebo. The volume of UNDW causing a 20% fall in FEV1 (UNDW PD20) was calculated by linear interpolation on the dose-response curve. UNDW response after placebo was not significantly different from the preliminary test (PD20 4.3 +/- 0.7 and 4.1 +/- 04 ml, respectively, mean +/- SE), whereas after L-ASA, UNDW PD20 increased to 17 +/- 2.7 ml (p < 0.01 vs placebo) and remained significantly increased after 24 hours. In another group of 12 patients under the same experimental conditions, an equivalent dose of inhaled sodium salicylate caused no effect. Finally, in a third group of asthmatic patients pretreatment with inhaled indomethacin at two dose levels (6 patients, 25 mg; 10 patients, 50 mg) resulted in a significant dose-related protective effect. These findings indicate that inhaled indomethacin and especially L-ASA exert against UNDW-induced bronchoconstriction a potent protective effect, which appears to be mediated by inhibition of local prostaglandin synthesis in the airways. This fact could have therapeutic implications.

Potentiation of the antireactive, antiasthmatic effect of inhaled furosemide by inhaled lysine acetylsalicylate.

Nonsteroid antiinflammatory drugs interfere with the diuretic activity of furosemide, implying that this effect is at least partially dependent on renal prostaglandin synthesis. To investigate whether prostaglandin production could also modulate the bronchial antireactive activity of this diuretic drug, we investigated the effect of inhaled Iysine acetylsalicylate (162 mg) and of furosemide (18 mg), alone and in combination, on the bronchial obstructive response to ultrasonically nebulized water in asthmatic patients. The study was also prompted by the conflicting results obtained in previous studies of oral nonsteroid antiinflammatory drugs. Fifteen asthmatic patients underwent bronchial challenge with a mist of ultrasonically nebulized distilled water at the same time of day on four occasions, 2–4 days apart, 15 min after premedication according to a double‐blind, randomized protocol. After placebo, mean PD15 to water mist did not differ from a preliminary test (2.1 ± 0.2 and 2.5 ± 0.4 ml, M ± SE, respectively). After lysine acetylsalicylate, mean PD., rose to 5.0 ± 0.7 ml (2.8 ± 0.6 times higher than placebo); after furosemide, to 9.0± 1.5 ml (4.4 ± 0.9 times over placebo); and after the two drugs in combination, to 32.2 ± 5.6 ml (16.3 ± 3.0 times higher than placebo). Similar results were obtained with inhaled indomethacin, whereas sodium salicylate had no effect. These data indicate that the bronchial antireactive activity of inhaled furosemide is greatly enhanced by inhaled lysine acetylsalicylate through a mechanism which probably involves inhibition of the local synthesis of prostaglandins, and could have therapeutic implications.

Protective effect of inhaled lysine acetylsalicylate on allergen-induced early and late asthmatic reactions ☆ ☆☆ ★

Conflicting results have been reported on the effect of non-steroidal antiinflammatory drugs on allergen-induced asthmatic responses. The aim of this study was to investigate the effect of inhaled lysine acetylsalicylate (LASA) on the early and late allergen-induced responses. We studied 16 patients with mild, stable asthma who had an early asthmatic response and 10 patients with a dual (early and late) response. Each patient underwent two challenges with a single dose of allergen assessed in a preliminary test, after inhalation of either 720 mg of LASA in 4 ml of saline solution or placebo, according to a randomized, double-blind protocol. Allergen-induced hyperreactivity to methacholine was measured in six patients from each of the early and the dual response groups 2 hours and 24 hours after the challenge, respectively. In the patients with early response, the maximum fall in FEV1 after challenge was 24% +/- 1% after inhalation of placebo and 14% +/- 2% after inhalation of LASA (p < 0.005). No protection was observed in four patients who received the drug orally instead of by inhalation. In the patients with a dual response, the maximum FEV1 decrease during the early response was 27% +/- 2% after placebo and 21% +/- 2% after LASA (p < 0.025). During the late response (between 3 and 8 hours), the maximum decrease in FEV1 was 28% +/- 4% after placebo and 16% +/- 4% after LASA (p < 0.005). In both groups allergen challenge caused a significant reduction in methacholine PD20 after treatment with placebo but not with LASA. Without allergen challenge, LASA had no effect on methacoline reactivity. We conclude that inhaled LASA significantly reduces both the early and the late asthmatic response to allergen challenge and that it prevents the allergen-induced airway hyperresponsiveness that follows these responses.

Time-limited protective effect of inhaled frusemide against aspirin-induced bronchoconstriction in aspirin-sensitive asthmatics

Inhaled frusemide effectively prevents the bronchial obstructive response to allergens and to a number of nonallergic stimuli. In most of the experimental models in which it has been tested, the protective effect of frusemide has been evaluated for only a short time after administration. In aspirin-sensitive patients, acetylsalicylic acid causes an asthmatic reaction which typically lasts for 2 h or more after exposure. We investigated the presence and duration of the protective effect of inhaled frusemide against the bronchial response to aspirin in sensitive patients, using a specific inhalation challenge with lysine acetylsalicylate (LASA). In the first study, eight subjects with aspirin-asthma underwent two bronchial challenges with a single dose of lysine acetylsalicylate administered through a jet nebulizer, after treatment with 40 mg inhaled frusemide or placebo, according to a randomized, double-blind protocol. Forced expiratory volume in one second (FEV1) was monitored for 120 min after challenge. In the second study in eight patients, the protocol was modified by the use of a dosimeter for delivery of lysine acetylsalicylate, by reducing the dose of lysine acetylsalicylate to avoid intense reactions, and by extending the follow-up to 4 h. In the first study, after placebo, FEV1 gradually decreased, reaching a maximum decrement of 39 +/- 3% at 120min. Inhaled frusemide exerted a significant protection at all time-points, although this activity appeared to decrease with time. In the second study, after placebo, inhaled lysine acetylsalicylate caused a gradual decrease in FEV1, which reached a maximum decrement at 180 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Exhaled nitric oxide in idiopathic and non-idiopathic interstitial lung disease

Background: Recently, fractional exhaled nitric oxide (FENO) has been studied as a potential marker of many interstitial lung diseases (ILD), such as idiopathic pulmonary fibrosis (IPF) or systemic sclerosis associated ILD, and their severity. Aim and Objectives: to investigate the role of FeNO in the differential diagnosis between ILDs. Methods: We measured FeNO at multiple flow-rates (50-100-150 and 350 ml/s) and alveolar concentration of NO (CalvNO) in 50 healthy controls and 135 patients affected by ILD: 50 with IPF, 20 with idiopathic non-specific interstitial pneumonia (NSIP), 20 with chronic hypersensitivitis pneumonia (cHP) and 45 with connective tissue disease related ILD (CTD-ILD). Receiver operating characteristic curves were conducted to evaluate diagnostic accuracy of eNO parameters for CTD-ILD. Results: ILD patients reported higher values of FeNO 150-350 and CalvNO than controls (CalvNO: p Conclusions: FeNO 150-350 and CalvNO levels are elevated in patients with ILD. Interestingly, patients with CTD-ILD showed the highest values, suggesting a possible role of NO in lung inflammation and fibrosis associated with rheumatological disease. Further studies are needed to confirm the potential role of CalvNO in discriminating between CTD and non-CTD-ILD.